related to vasoconstriction of nasal mucosal vessels leading to a decrease in the fluid content of the mucosa34.

Amazingly, little is known about the pathohistology and pathophysiology of the common cold. The beneficial effect of ipratropium bromide, which is a cholinoceptor antagonist, on the watery rhinorrhea in the first few days of a cold suggests that at least the early symptoms are reflexly mediated35. There is no convincing evidence that kinins and not histamine plays a major role in symptom production36.

Drugs administered for systemic effect

The nasal route is being actively developed as a method of delivering drugs to the systemic circulation. This route is easier and more comfortable for the patient than the parenteral route and it avoids enterohepatic recirculation and gut enzymes. This naturally makes it attractive for the delivery of peptides and recombinant DNA technology. However, absorption rates fall off sharply when the molecular weight exceeds 1000 Daltons37 which probably explains why desmopressin38 is delivered successfully (m. w. 1069 Daltons), whilst insulin (m. w. 6000 Daltons approx.) is not (Figure 9.4)39.

The nasal mucosa demonstrates typical absorption mechanisms. Water soluble drugs enter via passive diffusion through aqueous channels. As the diffusion path through the nasal mucosa is short, intranasally administered drugs demonstrate a rapid rise to peak plasma concentrations, but the rapid clearance from the mucosa limits available time for absorption. Amino acids such as tyrosine and phenylalanine are absorbed by active transport, presumably by similar mechanisms to those observed in the blood brain barrier.

Currently, commercial products which utilise this route for systemic delivery exist for some gonadorelin analogues, which are hypothalmic hormones. These include buserelin for dependent prostatic cancer, oestradiol dependent endometriosis and infertility, and nafarelin also for endometriosis and infertility. A number of other hormones are being investigated at a preliminary stage, including desmopressin for diabetes insipidus and primary nocturnal enuresis and lypressin for diabetes insipidus. Anterior pituitary hormones include LHRH

agonists and analogues which are used as contraceptive agents. Synthetic nasal salmon calcitonin is used in Hong Kong to treat ostoporosis40.

A nasally delivered live attenuated influenza vaccine (FluMist™) has been developed to aid annual immunisation for influenza particularly for children and the elderly41. It consists of egg allantoic fluid, primarily ovalbumin and live attenuated influenza viruses types A and B.

In the US, sufentanil and midazolam are administered intranasally for sedation. Antimigraine treatments such as ergotamine tartate, sumatriptan and butorphanol are also administered intranasally to relieve the nausea and vomiting which is associated with severe migraine.

Penetration enhancers

The drive to increase the absorption of large molecular weight molecules has lead to the use of penetration enhancers. Bile salts, e.g. sodium deoxycholate, sodium glycocholate and sodium taurocholate, decrease the viscosity of mucus and create transient hydrophilic pores in the membrane bilayer. EDTA, and fatty acid salts such as sodium caprate and sodium laurate, increase paracellular transport by removal of luminal calcium, thus increasing permeability of the tight junctions. Non-ionic detergents e.g. Laureth-9 alter membrane structure and permeability. It should be remembered that the penetration enhancers are generally non-specific and there remains the potential that any large molecule can enter the systemic circulation once the epithelial barrier is breached. Some penetration enhancers, e.g. Laureth-9 and bile salts, have been reported to be toxic to the nasal mucosa.

Cyclodextrins have been used as solubilizers and absorption enhancers for nasal drug delivery42. Methylated E-cyclodextrins have been used to promote absorption of peptides and proteins, but mainly in animals. Limited studies show that the cyclodextrins are well tolerated in humans43 44.

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